The National Institute of Environmental Health Sciences (NIEHS)
and the US Environmental Protection Agency (EPA), as part of
its Science to Achieve Results (STAR) program, invite research
grant
applications to conduct studies on the role of air pollutants,
especially particulate matter (PM), in cardiovascular illness
and mortality. A potentially important role of PM has been
suggested
in epidemiology studies showing increased cardiopulmonary-related
mortality and hospital admissions for cardiovascular disease
associated with increases in exposure to PM. The mechanisms
by which PM, or
other air pollutants, cause these toxic effects are not adequately
understood. It is likely that different mechanisms are responsible
for acute and chronic effects.

The objectives of this program are three fold. The first is to
encourage innovative, multidisciplinary in vitro and in vivo research,
in laboratory animals and humans, on the specific cellular, molecular
and physiologic mechanisms by which air pollutants mediate adverse
cardiovascular effects. Another key objective is to identify and
investigate factors that make individuals more susceptible to the
cardiovascular effects of air pollutants. In addition, the intent
is to encourage collaboration between investigators with expertise
in environmental health science and those with expertise in state-of-the-art
techniques and methodologies used in cardiology and/or cardiovascular
research.

This RFA will use NIH R01 and R21 (Exploratory/Developmental)
award mechanisms and EPA’s STAR program, administered in
accordance with 40 CFR Part 30 and 40. Funding to an individual
grantee will be provided by a single award from either NIH or EPA.

PURPOSE OF THIS RFA

The National Institute of Environmental Health Sciences (NIEHS)
and the US Environmental Protection Agency (EPA) invite research
applications to address the mechanisms by which air pollutants,
especially particulate matter, contribute to the development, progression,
or exacerbation of cardiovascular disease. The major purposes of
this initiative are to:

support innovative, multidisciplinary in vitro and in vivo
research, in laboratory animals and humans, on the specific cellular,
molecular,
and physiologic mechanisms by which air pollutants mediate
adverse cardiovascular effects;

identify and investigate factors, such as age, pre-existing
disease, and genetics, that make individuals more susceptible
to the cardiovascular effects of air pollutants; and

encourage collaboration between cardiovascular researchers
and environmental health researchers in the application of the
state-of-the-art
tools and models to the problem of environmentally related
cardiovascular disease.

RESEARCH OBJECTIVES

Cardiovascular disease (CVD) is the leading cause of death in
the U.S. According to the American Heart Association’s “Heart
Disease and Stroke Statistics -- 2003 Update,” in 2000 CVD
caused nearly 40% of all deaths, and was listed as primary or contributing
cause in about 60 percent. Furthermore, although overall death
rates from heart disease and stroke declined in the 1980s and 1990s,
heart failure emerged as a major chronic disease for older adults.
In addition to age, “traditional” risk factors for
CVD include lifestyle (such as smoking, physical inactivity, and
diet), serum lipids, gender, race, and family history (genetics).
However, these risk factors do not fully explain the etiology or
incidence of CVD, and recent data have indicated that exposure
to air pollutants is also a risk factor.

The strongest and most consistent association between air pollution
exposure and cardiovascular morbidity and mortality has been seen
for ambient particulate matter. Particulate matter (PM) is a mixture
of solid particles and liquid droplets that vary in size and origin.
It represents a broad class of chemically and physically diverse
substances. The concentration of PM in air varies across space
and time and is related to the source of the PM and the transformations
that occur in the atmosphere. Particles are generally classified
into three aerodynamic categories: Coarse PM (between 2.5 and 10
microns) is typically derived from attrition, erosion, or dispersion
of soil, road dust and construction debris or agglomeration of
smaller combustion particles. Ultrafine (smaller than 0.1 micrometers
in diameter) and fine PM (less than 2.5 micrometers) are emitted
or formed from combustion products of fossil fuels (e.g., from
vehicle engines, power plants, and refineries) and contain sulfate,
nitrate, chloride and ammonium compounds, carbon (soot), a spectrum
of organic compounds, and metals. (For additional information on
ambient PM, go to http://www.epa.gov/oar/aqtrnd97/brochure/pm10.html).

Large prospective epidemiologic studies have shown that living
in areas with higher levels of ambient particulate matter (PM)
is associated with an increased risk of premature cardiopulmonary
death. For example, the Harvard Six-Cities study followed 8111
subjects from six cities with varying levels of air pollution for
6 years, and reported a significant difference in the adjusted
mortality-rate ratios for all-cause and cardiopulmonary deaths
between the most and least polluted cities in the study. Likewise,
the American Cancer Society study followed over 500,000 individuals
from all 50 states and reported a 6% increase in cardiopulmonary
deaths for every 10 micrograms/m3 elevation in PM. Time series
and panel studies of daily mortality and hospital admissions have
also found a significant association with daily fluctuations in
ambient particulate matter concentrations.

Improved air quality appears to correlate with a decrease in cardiopulmonary
mortality. A ban on coal sales in Dublin in 1990 resulted in a
35.6 microgram/m3 (70%) average reduction in PM. Adjusted death
rates for respiratory and cardiovascular deaths over the 6-year
period after the ban declined by 15.5% and 10.3%, respectively,
as compared to the 6-year period before the ban.

The mechanisms by which PM, or other air pollutants, cause these
toxic effects are not adequately understood, and it is likely that
different mechanisms are responsible for acute and chronic effects.
In addition, PM consists of many different components, and different
components may affect cardiovascular disease by different mechanisms.
Anomalous stimulation of the autonomic nervous system, perhaps
via stimulation of afferent nerve endings in the lung, has been
proposed as one mechanism by which PM acutely affects cardiac physiology.
Cardiac responses to PM that have been reported in humans include
increased heart rate, decreased heart rate variability, increased
ST-segment depression greater than 0.1 mV during mild exercise
among subjects with established coronary heart disease, and increased
discharge of implanted cardiac-defibrillators. Studies of laboratory
animals exposed to concentrated ambient particulate matter and
other types of PM have found acute changes in cardiac function,
including elevation of the S-T segment, arrhythmia, increased pulmonary
artery systolic pressure, decreased cardiac output, decreased stroke
volume, and shortened refractory period.

Other mechanisms may also play a role in PM-induced adverse cardiovascular
outcomes. For instance, inflammatory and pro-inflammatory changes
in the lung have been suggested as contributing to PM-related CVD.
It has been proposed that reactive oxygen species (ROS) and other
active compounds such as inflammatory cytokines, which are produced
in the lung after exposure to PM, might be transported to the heart
and vascular tissues and exert detrimental effects there or might
stimulate other organs such as the liver to produce compounds that
affect the cardiovascular system. For example, elevated levels
of C-reactive protein, an inflammatory protein associated with
risk of CVD, have been associated with exposure to increased levels
of PM in humans. Likewise, exposure of humans and laboratory animals
to particulate material resulted in changes in blood coagulation
proteins (e.g., fibrinogen) and platelets that may lead to a hypercoagulable
state. Recent progress also indicates that thrombosis and inflammation
are closely related and interactive processes, and one may influence
the other.

Atherosclerosis is a common pathologic condition in most adults
that underlies many other cardiovascular diseases. There is evidence
that PM exposure might hasten the development of this condition.
For instance, in atherosclerosis-prone Watanabe rabbits, instillation
of suspended PM collected from the ambient environment enhanced
the progression of atherosclerosis. Likewise, polycyclic aromatic
hydrocarbons (PAHs), such as benzo(a)pyrene, which are components
of indoor and outdoor air pollution, have been shown in vitro to
alter the redox environment in vascular walls, activating signaling
pathways that can lead to proliferation of vascular smooth muscle
cells, one of the hallmarks of atherosclerotic changes in the vessel
wall. In addition, certain aldehydes, such as acrolein and butadiene,
are cardiovascular toxicants and have been shown to induce proliferation
of vascular smooth muscle cells as well. These aldehydes are present
in some work environments and in ambient air, and several are listed
as hazardous air pollutants in the Clean Air Act Amendments of
1990 (section 112(b)).

Research has also indicated that some individuals and groups are
more susceptible to the effects of PM than others. Epidemiologic
studies have identified individuals with cardiovascular and respiratory
diseases, elderly individuals, and children as being at greater
risk for adverse effects from PM exposure. For instance, a recent
study showed a higher risk of PM-related cardiovascular mortality
in elderly patients with pulmonary disease than in those without
pulmonary disease. Studies have also shown that animals with compromised
health, either genetically or experimentally induced, are more
susceptible to instilled or inhaled particles.

Inhalation of air pollutants and their impact on the lung has
long been a concern and the subject of intensive research. The
effects of air pollutants beyond the lung have not been readily
appreciated. It is only in recent years that cardiovascular endpoints
have come to command a more urgent focus, and clearly many questions
remain as to the role that these environmental agents play in CVD.
Epidemiology and clinical studies have indicated that exposure
to air pollutants can increase the risk for cardiovascular disease;
however, despite these compelling associations, relatively little
data exist on the mechanisms of action of these pollutants.

The primary objectives of this research program are to support
research that will better elucidate the mechanisms by which air
pollutants affect the cardiovascular system, resulting in increased
morbidity and mortality, and to define factors which lead to differential
susceptibility for certain groups and individuals. The research
should use appropriate, innovative models and model systems and
state-of-the-art technologies. In addition, because of the complex
nature of this area, development of multidisciplinary collaborations
is a second important objective. Therefore this RFA is designed
to foster collaborations of environmental health and cardiovascular
researchers, in order to promote the use of the most relevant,
state-of-the-art cardiovascular models and methodologies, in combination
with validated exposure methods to relevant air pollutants. The
use of laboratory animal models and techniques that have been used
successfully in cardiovascular research, but that may not have
been applied to environmentally related CVD, is encouraged. These
might include genetically manipulated rodent strains that are inherently
susceptible or resistant to pollutants, as well as large animal
models that more closely model the human cardiovascular system.
Also, the use of state-of-the-art cellular and molecular biology,
genetic and genomic, proteomic, and metabolic profiling technologies
is encouraged.

This RFA is designed to solicit proposals that would address one
or both of the following key questions:

What are the physiological, cellular, biochemical, molecular
mechanisms by which air pollutants adversely affect the cardiovascular
system, resulting in increased morbidity and mortality?

Who are the populations most susceptible to air pollutant-induced
cardiovascular effects and what are the underlying mechanisms
of this susceptibility?

The RFA solicits proposals on basic in vitro, animal, and controlled
human exposure studies, and small clinical studies. Studies should
be hypothesis driven and designed to identify or understand mechanisms
by which air pollutants adversely affect the cardiovascular system.
Proposals to screen chemicals for cardiovascular toxicity will
only be considered responsive if they are designed to better understand
how different PM components or their mixtures affect the cardiovascular
system. Proposals to study acute or chronic effects of PM are both
responsive. In addition, proposed air pollutant exposures are expected
to be environmentally relevant. An example of an environmentally
relevant exposure is ambient particulate matter. Use of laboratory-generated
particles would require a strong rationale as to its scientific
and environmental relevance. Similarly, studies proposing extremely
high doses, or use of instillation rather than inhalation, require
justification.

Examples of research that would be responsive to this RFA would
include, but not be limited to the following, as they relate to
air pollution exposure:

physiologic mechanisms that may induce
cardiac changes from neural networks
in the pulmonary
system -- either
locally or
via the central
nervous system

secondary effects of air pollutants (through
lung and blood) on the cardiovascular
system

The novel application of appropriate animal models, such as large
animals, naturally susceptible models (e.g., ApoE, LDL-R, spontaneously
hypertensive rats, and hyperlipidemic rabbits), and genetically
or pharmacologically manipulated or disease-induced models is encouraged.
The innovative use of in vitro models (e.g., isolated-perfused
hearts and cultured myocardial cells) is also encouraged.

To ensure that proposals address priority areas of research, studies
will be considered non-responsive if they include a large population-based
study design. Additionally, any of the following proposed air pollutant
exposures will be considered non-responsive:

Applications will be evaluated by an NIH-convened peer review
panel. Subsequent to peer review, meritorious applications will
be considered for funding by either EPA or NIEHS. Policies that
govern grant award programs of each agency will prevail for respective
sources of support. As an applicant you will be solely responsible
for planning, directing, and executing the proposed project. This
RFA is a one-time solicitation. Future unsolicited, competing-continuation
applications based on this project will compete with all investigator-initiated
applications and will be reviewed according to the customary peer
review procedures. The anticipated award date is August 2004. Applications
that are not funded in the competition described in this RFA may
be resubmitted as NEW investigator-initiated applications using
the standard receipt dates for NEW applications described in the
instructions to the PHS 398 application.

NIEHS and EPA intend to commit $2 million each in FY 2004 to
fund the first budget year of 10–15 new grants. Funding
to an individual grantee will be provided by a single award from
either NIH or the EPA STAR program. Applicants for R01 grants
may request up to four years of support and up to $250,000 per
year in direct costs. Applicants for R21 (Exploratory / Developmental)
applications are limited to two years of support and $150,000
per year in direct costs. Should an applicant plan to include
subcontracts to other institutions or organizations, only the
direct costs associated with the subcontracts will be used to
tally the direct costs that apply toward the cap. Because the
nature and scope of the proposed research will vary from application
to application, it is anticipated that the size and duration
of each award will also vary. Although the financial plans of
NIEHS and EPA provide support for this program, awards pursuant
to this RFA are contingent upon the availability of funds and
the receipt of a sufficient number of meritorious applications.

ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any
of the following characteristics:

Non-profit organizations. Applications will not be accepted
from for-profit organizations; however, organizations may establish
subcontract arrangements with for-profit organizations.

Public or private institutions, such as universities, colleges,
hospitals, and laboratories.

Domestic institutions. Applications will not be accepted from
foreign institutions; however, foreign institutions may
establish sub-contract arrangements with domestic applicant institutions.

Units of State and local governments.

Eligible agencies of the Federal government.

Non-profit faith-based or community-based organizations.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary
to carry out the proposed research is invited to work with his
or her institution to develop an application for support. Individuals
from underrepresented racial and ethnic groups as well as individuals
with disabilities are always encouraged to apply for NIH and EPA
programs.

SPECIAL REQUIREMENTS

Applications for R21 grants should be for new, highly innovative
research using models and technologies that have not been previously
applied to the field of environmentally related CVD.

Applications for R01 grants must be for collaborative research
between at least one investigator with expertise in environmental
health science and one investigator with demonstrated expertise
in state-of-the-art techniques and methodologies used in cardiology
and/or cardiovascular research. Applications not proposing such
a collaboration will be returned to the applicant.

All applicants should request funds for travel to attend a grantees’ meeting
approximately two years after the award of the grants. In addition,
applicants for R01 grants should request funds to attend a second
meeting approximately four years after the award of the grants.

Quality Assurance Statement: A Quality Assurance Statement (QAS)
must be submitted for each project proposed in any application
submitted in response to this RFA. This requirement results from
implementation of ANSI/ASOC E4, Specifications and Guidelines for
Quality Systems for Environmental Data Collection and Environmental
Technology Programs, and is available for purchase from the American
Society for Quality. Each QAS should not exceed two pages. This
Statement should, for each item listed below, present the required
information, reference the specific page and paragraph number containing
the information, or provide a justification of why the item does
not apply to the proposed research.

Identify the individual who will be responsible for the quality
assurance and quality control aspects of the research. (Quality
assurance (QA) is an integrated system of management activities
involving planning, implementation, documentation, assessment,
and improvement to ensure that a process, or item is of the type
and quality needed for the project. Quality control (QC) is the
system of technical activities that measures the attributes and
performance of a process or item against defined standards, to
verify that they meet the stated requirements.)

Discuss the activities to be performed or the hypothesis
to be tested and criteria for determining acceptable data quality.
(Note: Such criteria may be expressed in terms of precision,
accuracy,
representativeness, completeness, and comparability or in terms
of data quality objectives or acceptance and evaluation criteria.)
Also, these criteria must be applied to determine the acceptability
of existing, or "secondary," data to be used in the
project. (In this context, secondary data may be defined as data
previously
collected for other purposes or from other sources.)

Describe the study design. Include sample type(s) and location
requirements, all statistical analyses that were or will be
used to estimate the types and numbers of physical samples required,
or equivalent information for studies using survey and interview
techniques.

Describe the procedures that will be used in the calibration
and performance evaluation of all analytical instrumentation
and all methods of analysis to be used during the project. Explain
how the effectiveness of any new technology will be measured.

Describe the procedures for the handling and custody of
samples, including sample collection, identification, preservation,
transportation,
and storage, or how the accuracy of test measurements will
be verified.

Discuss the procedures for data reduction and reporting,
including a description of all statistical methods to make inferences
and
conclusions, with identification of any statistical software
to be used; discuss any computer models to be designed or utilized
and describe the associated verification and validation techniques.

Describe
the quantitative and/or qualitative procedures that will be
used to evaluate the success of the project, including
any plans for peer or other reviews of the study design or
analytical
methods prior to data collection.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial
or grants management issues:

Prospective applicants are asked to submit a letter of intent that
includes the following information:

Descriptive title of the proposed research

Name, address, and telephone number of the Principal Investigator

Names of other key personnel

Participating institutions

Number and title of this RFA

Although a letter of intent is not required, is not binding, and
does not enter into the review of a subsequent application, the
information that it contains allows staff at NIEHS and EPA to estimate
the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to:

Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001) and submitted
to the Center for Scientific Review, NIH. Applications must have
a DUN and Bradstreet (D&B) Data Universal Numbering System
(DUNS) number as the Universal Identifier when applying for Federal
grants or cooperative agreements. The DUNS number can be obtained
by calling (866) 705-5711 or through the web site at www.dunandbradstreet.com
. The DUNS number should be entered on line 11 of the face page
of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

Applications
requesting up to $250,000 per year in direct costs must be submitted
in a modular grant format. The modular grant format simplifies
the preparation of the budget in these applications by limiting
the level of budgetary detail. Applicants request direct costs
in $25,000 modules. Section C of the research grant application
instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes
step-by-step guidance for preparing modular grants. Additional
information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL

The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the
face page of the application. Type the RFA number on the label.
Failure
to use this label could result in delayed processing of the application
such that it may not reach the review committee in time for review.
In addition, the RFA title and number must be typed on line 2
of the face page of the application form and the YES box must be
marked.
The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

SENDING AN APPLICATION TO THE NIH

Submit a signed, typewritten
original of the application, including the Checklist, and three
signed, photocopies, in one package to:

Applications must be received on or before
the application receipt date listed in the heading of this
RFA. If an application is received after that date, it will be
returned
to the applicant without review.

Although there is no immediate acknowledgement of the receipt
of an application, applicants are generally notified of the review
and funding assignment within 8 weeks.

The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. However, when a previously unfunded application,
originally submitted as an investigator-initiated application,
is to be submitted in response to an RFA, it is to be prepared
as a NEW application. That is, the application for the RFA must
not include an Introduction describing the changes from the previous
unfunded version of the application.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness
by the CSR and responsiveness by the NIEHS and EPA. Incomplete
applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may
contact the applicant to determine whether to return the application
to the applicant or submit it for review in competition with unsolicited
applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will
be evaluated for scientific and technical merit by an appropriate
peer review group convened by the NIEHS in accordance with the
review criteria stated below. As part of the initial merit review,
all applications will:

Undergo a process in which only those applications deemed
to have the highest scientific merit, generally the top half
of the
applications under review, will be discussed and assigned a
priority score

Receive a written critique

Receive a second level review by the NIEHS National Advisory
Council or by EPA’s National Center for Environmental Research.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health. In the written comments, reviewers will be asked to evaluate
the application in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of these
goals. The scientific review group will address and consider each
of the following criteria in assigning the application’s
overall score, weighting them as appropriate for each application.

Significance

Approach

Innovation

Investigator

Environment

The application does not need to be strong in all
categories to be judged likely to have major scientific impact
and
thus deserve a high priority score. For
example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move
a
field forward.

SIGNIFICANCE

Does this study address important research objectives
related to the impact of air pollutants on cardiovascular disease?
If the aims of the application are achieved, how will scientific
knowledge be advanced? What will be the effect of these studies
on the concepts or methods that drive this field?

APPROACH

Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the
aims of the project? Does the applicant acknowledge potential problem
areas and consider alternative tactics? Is there clear evidence
of significant interdisciplinary interactions in the conception,
design, and proposed implementation of the project?

INNOVATION

Does the project employ novel concepts, approaches
or methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?

INVESTIGATOR(S)

Are the investigators appropriately trained and
well suited to carry out this work? Is the work proposed appropriate
to the experience level of the principal investigator and other
researchers (if any)?

ENVIRONMENT

Does the scientific environment in which the work
will be done contribute to the probability of success? Do the
proposed experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support?

ADDITIONAL REVIEW CRITERIA

In addition to the above criteria,
the following items will be considered in the determination of
scientific merit and the priority score:

For R01 grant applications: Are both environmental health science
and cardiovascular researchers included in the application, and
is there adequate evidence that a productive collaboration is likely?

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK

The involvement
of human subjects and protections from research risk relating
to their participation in the proposed research will be assessed.
(See criteria included in the section on Federal Citations, below).

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH

The
adequacy of plans to include subjects from both genders,
all racial and ethnic groups (and subgroups), and children as appropriate
for the scientific goals of the research. Plans for the recruitment
and retention of subjects will also be evaluated. (See Inclusion
Criteria in the sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH

If vertebrate
animals are to be used in the project, the five items described
under Section f of the PHS 398 research grant application instructions
(rev. 5/2001) will be assessed.

ADDITIONAL REVIEW CONSIDERATIONS

Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any
year of the proposed research are expected to include a data sharing
plan in their application. The reasonableness of the data sharing
plan or the rationale for not sharing research data will be assessed
by the reviewers. However, reviewers will not factor the proposed
data sharing plan into the determination of scientific merit or
priority score.

BUDGET

The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.

EPA Programmatic Review: Applications that are considered meritorious
by the peer reviewers are subjected to a programmatic review within
the EPA to assure a balanced research portfolio for the Agency.
Applications are then recommended for funding to the NCER Director
who makes funding decisions. Applications are selected for an award
based on consideration of the scientific quality of proposals and
relevance to EPA program research priorities, program balance,
budget, and available funds.

REQUIRED FEDERAL CITATIONS

HUMAN SUBJECTS PROTECTION

Federal regulations (45CFR46) require
that applications and proposals involving human subjects must
be evaluated with reference to the risks to the subjects, the adequacy
of protection against these risks, the potential benefits of
the
research to the subjects and others, and the importance of the
knowledge gained or to be gained.http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm

Starting with the October 1, 2003 receipt
date, investigators submitting an NIH application seeking more
than $500,000 or more in direct costs in any single year are
expected to include a plan for data sharing or state why this is
not possible.
http://grants.nih.gov/grants/policy/data_sharing Investigators
should seek guidance from their institutions, on issues related
to institutional policies, local IRB rules, as well as local,
state and Federal laws and regulations, including the Privacy Rule.
Reviewers
will consider the data sharing plan but will not factor the plan
into the determination of the scientific merit or the priority
score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH

It is the policy of the NIH that women and members of minority
groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification
is provided indicating that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the
research.
This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in
the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a
complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The
amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance
with the new OMB standards; clarification of language governing
NIH-defined Phase III clinical trials consistent with the new PHS
Form 398; and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all
NIH-defined Phase III clinical trials that: a) all applications
or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if
applicable; and b) investigators must report annual accrual and
progress in conducting analyses, as appropriate, by sex/gender
and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS

The NIH maintains a policy that children (i.e., individuals
under the age of 21) must be included in all human subjects research,
conducted or supported by the NIH, unless there are scientific
and ethical reasons not to include them. This policy applies
to all initial (Type 1) applications submitted for receipt dates
after
October 1, 1998.

NIH policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for
research involving human subjects. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June
5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC)

Criteria for federal funding
of research on hESCs can be found at http://stemcells.nih.gov/index.asp and
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only
research using hESC lines that are registered in the NIH Human
Embryonic Stem Cell Registry will be eligible for Federal
funding
(see http://escr.nih.gov).
It is the responsibility of the applicant to provide, in the
project description and elsewhere in the application
as appropriate, the official NIH identifier(s) for the hESC line(s)to
be used in the proposed research. Applications that do not provide
this information will be returned without review.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION
ACT

The Office of Management and Budget (OMB) Circular A-110 has
been revised to provide public access to research data through
the Freedom of Information Act (FOIA) under some circumstances.
Data that are (1) first produced in a project that is supported
in whole or in part with Federal funds and (2) cited publicly
and officially by a Federal agency in support of an action that
has
the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the
basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a
public archive, which can provide protections for the data and
manage the distribution for an indefinite period of time. If so,
the application should include a description of the archiving plan
in the study design and include information about this in the budget
justification section of the application. In addition, applicants
should think about how to structure informed consent statements
and other human subjects procedures given the potential for wider
use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION

The Department of Health and Human Services (DHHS) issued final
modification to the “Standards for Privacy of Individually
Identifiable Health Information”, the “Privacy Rule,” on
August 14, 2002. The Privacy Rule is a federal regulation under
the Health Insurance Portability and Accountability Act (HIPAA)
of 1996 that governs the protection of individually identifiable
health information, and is administered and enforced by the DHHS
Office for Civil Rights (OCR). Those who must comply with the Privacy
Rule (classified under the Rule as “covered entities”)
must do so by April 14, 2003 (with the exception of small health
plans which have an extra year to comply).

Decisions about applicability and implementation of the Privacy
Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/) provides
information on the Privacy Rule, including a complete Regulation
Text and a set of decision
tools on “Am I a covered entity?” Information on the
impact of the HIPAA Privacy Rule on NIH processes involving the
review, funding, and progress monitoring of grants, cooperative
agreements, and research contracts can be found at http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES

All applications
and proposals for NIH funding must be self-contained within specified
page limitations. Unless otherwise specified in an NIH solicitation,
Internet addresses (URLs) should not be used to provide information
necessary to the review because reviewers are under no obligation
to view the Internet sites. Furthermore, we caution reviewers
that their anonymity may be compromised when they directly access
an
Internet site.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed
to achieving the health promotion and disease prevention objectives
of "Healthy People 2010," a PHS-led national activity
for setting priority areas. This RFA is related to one or more
of the priority areas. Potential applicants may obtain a copy of "Healthy
People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS

This program is described in the Catalog
of Federal Domestic Assistance at http://www.cfda.gov/ and
is not subject to the intergovernmental review requirements of
Executive
Order 12372 or Health Systems Agency review. Awards are made
under
the authorization of Sections 301 and 405 of the Public Health
Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. Awards by EPA
are made under
the authority of 40 CFR Part 30 and 40 and are subject to terms
and conditions and other considerations that can be found at
http://www.epa.gov/ncer/guidance/.
All awards made by NIEHS are subject to the terms and conditions,
cost principles, and other considerations described in the NIH
Grants Policy Statement. The NIH Grants Policy Statement can
be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS and EPA strongly encourage all grant recipients to provide
a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education, library,
day care, health care, or early childhood development services
are provided to children. This is consistent with the PHS mission
to protect and advance the physical and mental health of the American
people.